Diabetes is the leading cause of chronic kidney disease (CKD), and with hypertension accounts for more than two-thirds of risk for cardiovascular disease, the leading cause of death in industrialized nations. Hypertension in diabetes and obesity, including resistant patients, is remarkably responsive to aldosterone, i.e. mineralocorticoid, receptor (MR) blockade, even if plasma aldosterone is not elevated. A critical barrier to progress is understanding mechanisms for the augmented MR-dependent control of sodium reabsorption in diabetes in the absence of overt hyperaldosteronism. The MR is the main regulator of ENaC-dependent Na+ transport in the distal nephron. ENaC also can be activated by insulin, and insulin has long been hypothesized to be antinatriuretic. However, until our recent studies in dogs there was no direct evidence outside of rodent models for chronic sodium retaining or hypertensive actions of insulin. In fact, all previous chronic dog and human data refuted the insulin hypothesis. Our objective in this renewal is to determine whether insulin+glucose stimulation of sodium reabsorption via ENaC overcomes the critical barrier to progress in understanding mechanisms for the augmented MR-dependent control of sodium reabsorption in diabetes independent of overt hyperaldosteronism. Our central hypothesis is that increased insulin and glucose act cooperatively to increase renal sodium reabsorption via ENaC in uncontrolled Type II diabetes. We predict that this sodium retaining action is a newly-revealed, physiologic mechanism to preserve sodium balance in uncontrolled Type II diabetes, but it is maladaptive and pro-hypertensive in the face of other renal impairments. Our specific aims are to: 1) Test the hypothesis that the chronic antinatriuretic effect of insulin+glucose in diabetes depends significantly on ENaC., and 2) Test the hypothesis that the sodium retaining action of insulin+glucose in diabetes causes hypertension in the presence of an underlying sodium-retaining shift in kidney function. Thisprojectintegrates work in chronically-instrumented dogs, collecting duct cell culture, patch-clamp of dog cortical collecting duct, and renal immunohistochemistry and Western analysis for ENaC and SGK1. This integrated approach has significant advantages over existing alternatives. When the aims are achieved, scientific knowledge and clinical practice with respect to understanding the mechanisms for chronic regulation of sodium balance and blood pressure by insulin in diabetes will be improved. For example, use of existing treatments, such as ENaC inhibitors and aldosterone receptor blockers, may be modified in obese and diabetic patients. In addition, we are discovering new physiology on the chronic regulation of sodium balance by insulin in diabetes that will underlie and direct investigations for new treatments.